The invention relates in general to batch biological and chemical and analysis of large numbers of samples. More specifically it relates to a fast response thermal cycler that carries a large batch of samples through one or more predetermined temperature profiles.
In biological and chemical testing and experiments it is often necessary to repeatedly cycle samples of a biological specimen or chemical solution through a series of different temperatures where they are maintained at different set temperatures for predetermined periods of time. While single sample processing can be used, many experiments, particularly ones in modern biological experimentation, require the use of large numbers of samples. Modern biological testing often uses micro-titration plates. A standard such plate is a plastic sheet with 96 depressions, each adapted to hold one of the samples to be processed. The plastic is sufficiently thin that the sample can readily reach a thermal equilibrium with a conductive mass at the opposite face of the plastic sheet. Testing also often requires a large number of cycles in each experiment, e.g. fifty. For cost effective processing it is therefore important to reach and stabilize at a set temperature rapidly. It is also cost effective, and sometimes necessary, to process a large number of samples in each experimental run. A plate of 96 samples is more cost effective than the processing of samples one by one.
Various devices and techniques are known for the thermal cycling of multiple samples. The most common technique utilizes thermoelectric devices. The apparatus sold by M. J. Research Inc. under the trade designation "Minicycler" is typical. It uses all solid state electronics and the Peltier effect. Conventional refrigeration techniques are also known, as is the combination of electrical heating and water cooling, as used in a device sold by Stratagene Inc. under the trade designation Temperature Cycler SCS-96.
These devices operate reasonably well, but they operate on only one plate. One problem with somehow expanding these devices to handle multiple plates is that a uniform temperature profile for a large number of plates requires multiple temperature sensing devices at various locations and a way to vary the temperature quickly and reliable at any portion of the samples. Another problem is that any malfunction or diminution of function of any component requires a repair of a complex system that extends over this large area. Repairs can disable the entire unit, and they can be slow and expensive. A further problem is that known cyclers, regardless of claims to be able to move to a new temperature rapidly, are nevertheless comparatively slow, regardless of the number of plates being processed. For example, a typical thermoelectric unit takes 210 to 230 seconds to go from room temperature to 94.degree. C. and stabilize there. If an experiment requires 50 different temperature cycles of this magnitude, then 3 to 4 hours is used just in cycling to new temperatures. This is a significant source of delay in conducting the experiment, and a significant element of cost.
It is therefore the principal object of the invention to provide a thermal cycler and a method of operation with a high sample volume, good temperature control, and fast response time to yield a high throughput that is multiple times greater than throughputs attainable heretofore.
Another object of this invention is to provide a foregoing advantages while also providing extreme ease of maintenance of the cycler.
A further object is to provide a cycler which is highly flexible and can be adapted to process a variety of sample holders, or to receive the samples directly.
Still another object is that it provides the foregoing advantages while also allowing the simultaneous running of different temperature profiles.